This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Diabetes mellitus is a metabolic disease affecting an estimated 8% of the population of 25% of those over age 65 in the United States. The disease arises from a dysregulation of the hormone insulin, which is responsible for regulating the level of blood sugar (glucose) in circulation. Sustained hyperglycemia (elevated glucose levels) is a leading cause of neuropathy, kidney failure, blindness, and cardiovascular disease, while a hypoglycemic condition (low glucose levels) causes neurological symptoms and even coma. The current management of the disease involves a combination of drugs which increase either endogenous insulin secretion or the efficiency of insulin uptake. However, many of these drugs also have undesired side effects such as weight gain or intolerable nausea, leading many to opt to the terminal treatment of insulin injections. Over time, the amount of insulin required for injections increases due to desensitization, diminishing the efficacy of treatment. Thus, the development of new medications which avoid unpleasant side effects is needed. One promising drug target is a protein called protein tyrosine phosphatase 1B (PTP1B), which has been found to specifically bind to and inhibit the insulin receptor protein kinase domain (IRK). Inhibitors of PTP1B in animal studies have been found to improve insulin sensitization without the side effect of weight gain. However, the mechanism by which PTP1B actually binds to insulin receptor is unknown. Here we propose a series of long timescale MD simulations on a recently solved PTP1B-IRK complex to uncover the mechanism by which PTP1B binding to IRK destabilizes the insulin receptor's phosphorylated signaling domain. The key discoveries from these simulations should assist in the rational design of effective PTP1B inhibitors.